Inhibition of colon carcinogenesis by 2-methoxy-5-amino-N-hydroxybenzamide, a novel derivative of mesalamine.
Gastroenterology
; 138(1): 221-30, 2010 Jan.
Article
em En
| MEDLINE
| ID: mdl-19737563
ABSTRACT
BACKGROUND & AIMS:
Mesalamine has been reported to protect against inflammatory bowel disease-related colorectal cancer (CRC), but several drug-related issues have limited its use in chemopreventive programs. We evaluated the antineoplastic properties of mesalamine derivatives using in vitro and in vivo models of CRC.METHODS:
CRC cell proliferation and cell-cycle progression were evaluated by flow cytometry after exposure to mesalamine or mesalamine derivatives. Cyclins, cyclin-dependent kinases, and endoplasmic reticulum stress-related molecules were examined by immunoblotting. The in vivo antineoplastic effect of 2-methoxy-5-amino-N-hydroxybenzamide (2-14) was evaluated in a syngenic, CT26-derived xenograft mouse model of CRC and in the azoxymethane/dextran sulfate sodium-induced mouse model of colitis-associated CRC.RESULTS:
The mesalamine derivative 2-14 was 10-fold more potent than mesalamine in inhibiting CRC cell proliferation. After exposure to 2-14, cyclin D1 expression was reduced and G0/G1 phase cells accumulated. These events were preceded by activation of eukaryotic translation initiation factor 2-alpha kinase 3 (pancreatic endoplasmic reticulum eIF2alpha kinase), phosphorylation of eukaryotic translation initiation factor 2alpha, induction of activating transcription factor 4, and splicing of X-box binding protein 1 messenger RNA, events that define endoplasmic reticulum stress. Silencing of PERK restored cyclin D1 levels, allowing cells to overcome the cell-cycle block induced by 2-14. Mice injected with 2-14 developed fewer CRC xenograft-derived tumors. Moreover, 2-14 injection reduced the development of neoplastic lesions induced by azoxymethane and dextran sulfate sodium in mice.CONCLUSIONS:
The mesalamine derivative 2-14 inhibited CRC cell proliferation in vitro and prevented CRC progression in mouse models.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Colite
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Neoplasias do Colo
/
Ácidos Aminossalicílicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article